This invention relates to a method for the preparation of DL-carnitine hydrochloride and in particular to a novel synthetic method for preparing DL-carnitine nitrile halide which is an intermediate for DL-carnitine hydrochloride.
The chemical nomenclature of said DL-carnitine hydrochloride is DL-gamma-trimethylammonium-beta-hydroxybutyrate hydrochloride and is represented by the following structural formula: ##STR1## The carnitine nitrile halide is more properly referred to as DL-gamma-trimethylammonium-beta-hydroxybutyronitrile chloride and is represented by the following structural formula: ##STR2## As used hereinbelow, the conventional designation of "carnitine" will be used in place of the rather lengthy designation DL-carnitine hydrochloride or its chemical name. Also, "carnitine nitrile halide" will be used herein instead of the lengthy designation or the chemical name of the intermediate for producing carnitine.
Carnitine is a substance that was found in the muscle extract of mammals by Gulevisch and Krimberg (Z. Physiol. Chem., 45, 326), and by Kutscher (Z. Untersuch. Nahr. u. Genussm., 10, 528) in 1905. The constitutional formula of carnitine was determined by Tomita and others in 1927. In 1952, carnitine was proved by Carter et al to be the same substance as vitamin B.sub.T, a new member of the vitamin B group, which has been discovered by Fraenkel et al in 1948.
Numerous studies have been made on the physiological and pharmacological actions of Vitamin B.sub.T, i.e., carnitine.
The preparative methods of carnitine may be divided into two classes, that is, an extracting process from natural materials and a chemical synthesis. A number of methods have been proposed up to the present. The extracting process from natural materials, however, does not go beyond the laboratory scale. On the other hand, the synthetic method, which is now considered to be successful to a certain extent, includes many difficulties, such as, an extremely low yield and a large amount of by-products. These difficulties make it practically impossible to obtain a product of high purity.
The method of Friedman [Biochem. Preparations, 6 (1958)] is an example of the extracting processes from natural sources. According to this method, carnitine is isolated from beef extract by treating with organic solvents, ion-exchange resins and other agents, but the yield of carnitine is only about 7 grams based on 450 grams of beef extract. The method devices by Carter and Bhattacharyya [J. Amer. Chem. Soc., 75, 2503 (1953)] is an example of the synthetic methods. According to this method, carnitine is to be synthesized from benzaldehyde and epichlorohydrin, through several steps. The final yield of carnitine is but ca. 20-25 percent. The method by Dechamps and others [Compt. rend., 283, 826 (1954)] is another example of a synthetic method, in which gamma-chloro-beta-hydroxybutyronitrile that has been preliminarily synthesized is made to react with trimethylamine, and the reaction product hydrolyzed under pressure to produce dicarnitine, but the yield is only ca. 20 percent.
More recently, Noguchi et al, U.S. Pat. No. 3,135,788, has substantially increased yields by reacting the halohydrin with trimethylamine hydrochloride to produce a 3-halo-2-hydroxypropyl trimethylammonium chloride which has been reacted with sodium or potassium cyanide to produce a 3-cyano-2-hydroxypropyl trimethylammonium chloride and alkali metal halide by-product, followed by hydrolysis to produce carnitine. Yields up to 85 percent in the crude product and about 75 percent in the refined product have been achieved. Also, (2,3-epoxypropyl)trimethylammonium chloride has been prepared in high yield and purity from epichlorohydrin and trimethylamine by reacting in an organic solvent, J. D. McClure, J. Org. Chem., 35, No. 6, 2059 (1970). Apparently, the use of an organic solvent rather than an aqueous liquid reaction medium preserves the epoxide ring rather than producing the 2-hydroxy-3-chloro compound, as occurs in Noguchi et al. It now has been found that the compound prepared by McClure can be employed in the synthetic preparation of carnitine nitrile chloride to achieve almost quantitative yield. Using this novel procedure as more fully described hereinbelow, the formation of water-soluble alkali metal halide is avoided. This is significant because the carnitine nitrile chloride is also water-soluble. Thus, avoiding the formation of alkali metal halide and its subsequent removal from the reactor and separation from the product, carnitine nitrile chloride results in a much cleaner product and quantitative yield.